title: Synthesis and structure-activity relationships of phenyl-substituted coumarins with anti-tubercular activity that target FadD32.
abstract: In an effort to develop new and potent agents for therapy against tuberculosis, a high-throughput screen was performed against Mycobacterium tuberculosis strain H37Rv. Two 6-aryl-5,7-dimethyl-4-phenylcoumarin compounds 1a and 1b were found with modest activity. A series of coumarin derivatives were synthesized to improve potency and to investigate the structure-activity relationship of the series. Among them, compounds 1o and 2d showed improved activity with IC90 of 2 μM and 0.5 μM, respectively. Further optimization provided compound 3b with better physiochemical properties with IC90 0.4 μM which had activity in a mouse model of infection. The role of the conformation of the 4- and 6-aryl substituents is also described.
authors.affiliation: The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Center for Computational and Integrative, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Department of Microbiology and Immunobiology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Kawate
authors.forename: Noriaki
authors.initials: N
authors.lastname: Iwase
authors.forename: Motohisa
authors.initials: M
authors.lastname: Shimizu
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Stanley
authors.forename: Samantha
authors.initials: S
authors.lastname: Wellington
authors.forename: Edward
authors.initials: E
authors.lastname: Kazyanskaya
authors.forename: Deborah T
authors.initials: DT
authors.lastname: Hung
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D003374:Coumarins
keywords: Coumarin; Inhibitor; Mycobacterium tuberculosis; Structure–activity relationship (SAR)